The goal of this application is to develop a genetically engineered therapeutic human skin substitute with enhanced antimicrobial and angiogenenic properties for use in the treatment of type 1 diabetic skin ulcers. Chronic diabetic skin ulcers exhibit poor blood flow and typically become infected resulting in impaired wound healing and amputation, a life threatening complication of diabetes. The standard of care for chronic, infected, nonhealing diabetic wounds is antibiotic treatment and synthetic dressings. Because bacterial strains typically encountered often become antibiotic resistant, especially in the chronic wound, the clinician is limited to more potent antibiotics with undesirable effects on viability and migration of cells in the diabetic skin ulcer. This, coupled with the growing concern over emerging new multi-resistant strains of bacteria, underscores the need for innovative approaches to supplement antibiotic treatment regimes used in open wound therapy. Stratatech Corporation's strategy to promote wound healing in infected diabetic skin ulcers is to develop a novel human skin substitute possessing a range of enhanced antimicrobial, re-epithelialization, and vascularization properties. Our FastTrack SBIR proposal outlines proven strategies for the generation of human skin substitutes genetically engineered to secrete biologically active antimicrobial peptides (AMPs) capable of stimulating vascularization and cell migration. Animal models of type 1 diabetes and chronic wound healing will be used to test the hypothesis that a human skin substitute tissue containing human AMPexpressing cells will prevent chronic wound infection, facilitate re epithelialization, and vascularization, and thus provide an optimal environment for the healing of diabetic wounds. Advances in ex vivo genetic engineering of a patented human keratinocyte cell line at Stratatech Corporation has made our young company uniquely positioned to generate genetically enhanced human skin substitutes for use in the treatment of type 1 diabetic skin ulcers.